This revised proposal seeks support for an investigator-initiated research project into the cellular and molecular means used by intermediate hosts of a human parasite to immunologically attack and kill these parasites. The broad, long-term objective is to break the cycle of parasite transmission to at-risk human populations. The research builds on recent progress in the applicant's laboratory and other laboratories, and exploits the principles of comparative functional genomics and an emerging database for the host snail's genome. In particular, the research deals with genes, messenger RNAs and proteins involved in the cellular respiratory burst - a complex pathway in which damaging reactive oxygen and nitrogen species are produced by the defense cells of the host and which are at least partialy responsible for the capacity of individual snails to resist infection. The aims address plausible hypotheses dealing with (i) genes: details of gene structure, transcription and post-transcriptional editing, (ii) proteins (including enzyme activities), (iii) activation pathways for cell responses, and (iv) ultimate causes of death of sporocysts. The hypotheses are both tractable and reasonably anchored in already demonstrated phenomena. Experimental materials include individual Biomphalaria glabrata snails with known susceptible or resistant phenotypes to a standard strain (Oregon PR1) of Schistosoma mansoni, a causative agent of human intestinal schistosomiasis. Funds will enable a team of researchers to focus their efforts on these issues over 5 years. Knowledge resulting from the studies is expected to enhance the likelihood of achieving a mission of this agency - prevention of future transmission of schistosome parasites (S. mansoni) to humans - accomplished by interruption of the parasite's life cycle in its intermediate host, B. glabrata. These goals will be addressed using inbred strains of the intermediate host snail species for which we have the necessary genetic information (nucleic acid sequence data) and in which it is now feasible to use sensitive reporters for and efficient inhibitors of a variety of cell functions. PUBLIC HEALTH RELEVANCE: The burden of this (human blood-fluke) parasite is considerable among human populations in endemic regions (>70 countries in which ~200,000,000 people are infected). Infected individuals experience lower levels of cognition (it is harder to learn), and of energy to do physical work. Hence this work, in which the ultimate aim is to break the cycle of schistosome transmission, may contribute to public welfare through enhancement of health and of the quality of life (improved capacities to learn and to do physical work).